The present invention is concerned with a process for obtaining diacetylrhein of pharmaceutically usable purity with a residual content of undesired aloe-emodin derivatives of, in all, less than 20 ppm, the diacetylrhein obtainable according to this process and a pharmaceutical composition which contains this compound.
Diacetylrhein of the formula: 
is a medicinally-active compound which possesses antiarthritic, anti-inflammatory, antipyretic and analgesic activity. Therefore, diacetylrhein is used for the treatment of arthritic diseases (cf., for example DE-A-27 11 493 and U.S. Pat. No. 4,244,968).
Diacetylrhein can be prepared, for example, by the acetylation of barbaloin and oxidation of the peracetylated barbaloin obtained with chromium trioxide. Furthermore, diacetylrhein can be prepared by the acetylation of rhein which can be obtained, for example, from senna drug.
Diacetylrhein obtained according to these processes contains undesired accompanying aloe-emodin derivatives which result from an incomplete oxidation with chromium trioxide or are co-extracted in the case of the extraction of senna drug. These accompanying materials are present in relatively small amounts and can, therefore, only be separated with great difficulty by means of well-known purification procedures. Furthermore, in the case of the first of the above-mentioned processes, chromium residues are present which have to be removed in appropriate manner.
Therefore, it is an object of the present invention to provide a process for obtaining diacetylrhein which is simple to carry out and gives high yields and in which diacetylrhein is obtained of pharmaceutically usable purity with a residual content of undesired aloe-emodin derivatives of, in all, less than 20 ppm.
Thus, according to the present invention, there is provided a process for obtaining diacetylrhein, wherein diacetylrhein containing aloe-emodin derivatives (i.e. aloe-emodin and/or derivatives thereof) is subjected to a liquidxe2x80x94liquid partitioning between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
A diacetylrhein containing aloe-emodin can be used in the process according to the present invention. Important sources of diacetylrhein are the senna drug-containing sennosides, as well as the rhein-9-anthrone-8-glucoside obtainable from the sennosides.
Therefore, a preferred embodimental form of the present invention is a process for the preparation of diacetylrhein which is substantially free from aloe-emodin derivatives, wherein
a) rhein-9-anthrone-8-glucoside containing aloe-emodin components is oxidised to the corresponding anthraquinone compounds,
b) the glucose residue in the 8-position of the anthraquinone compounds is split off in an acid medium,
c) the 1,8-dihydroxyanthraquinone compounds obtained are acetylated and
d) a liquidxe2x80x94liquid partitioning of the product obtained is carried out between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
Another preferred embodiment of the present invention is a process for the preparation of diacetylrhein which is substantially free from aloe-emodin derivatives, wherein
a) a sennoside mixture is subjected to a reduction to the corresponding anthrone compounds,
b) the anthrone compounds obtained are oxidised to the corresponding anthraquinone compounds,
c) the glucose residue in the 8-position of the anthraquinone compounds is split off in an acid medium,
d) the 1,8-dihydroxyanthraquinone compounds obtained are acetylated and
e) a liquidxe2x80x94liquid partitioning of the product obtained is carried out between a polar organic solvent which is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5 and the diacetylrhein is recovered and optionally recrystallised.
In the following, the individual steps of the process according to the present invention are explained in more detail:
The sennoside mixture used as starting material can be obtained, for example, from senna drug. The senna drug consists of the dried leaves and fruits of the senna plant, for example of the Indian senna (Cassia angustifolia) and Egyptian senna (Cassia acutifolia). The senna drug contains dianthrone glucosides of rhein and aloe-emodin. The most important ones are sennosides A, B, Al, C, D and Dl. The sennosides correspond to the general formula: 
In the case of sennosides A, B and Al, R stands for COOH and in the case of sennosides C, D and Dl, R stands for CH2OH. The sennosides A, B and Al and the sennosides C, D and Dl are stereoisomers and differ from one another by the configuration on carbon atoms 10 and 10xe2x80x2.
The obtaining of sennosides from senna drug is described, for example, in DE-A-32 00 131, reference to which is here made to the complete specification. According to this, the senna drug is first extracted with aqueous methanol. The concentrate remaining after complete removal of the methanol contains the sennosides in the form of alkali metal salts, preferably potassium salts. The concentrate is purified by liquidxe2x80x94liquid extraction with alcohols or ketones, for example butan-2-ol or butan-2-one, which are partly soluble in water (raffinate). The raffinate is acidified to a pH value of about 1.5 to 2.0 and the sennosides are crystallised by seeding out. The crude sennoside mixture obtained can be used as starting material for the process according to the present invention. If desired, the crude sennoside mixture can also be recrystallised.
Alternatively, the concentrate mixed with an alcohol which is only partly soluble in water, especially butan-2-ol, can be used as starting material for the process according to the present invention.
In the case of the extraction of the senna drug, the ratio of drug to extraction agent is preferably 1:4 to 1:15 and especially 1:4 to 1:10.
The extraction is preferably carried out in the presence of a buffer, for example trisodium citrate, glycine, sodium bicarbonate or saccharose.
According to the process of the present invention, these starting materials are reduced to give rhein-9-anthrone-8-glucoside (R=COOH) and aloe-emodin-9-anthrone-8-glucoside (R=CH2OH) of the general formula: 
wherein R is COOH or CH2OH.
Reducing agents with an appropriate reducing potential include stannous chloride, sulphur dioxide, alkali metal borohydrides and preferably alkali metal dithionites, especially sodium dithionite. The reducing agent is used in large excess. In general, a dithionite and especially sodium dithionite is used in a 1 to 4 fold amount by weight, referred to the content of sennosides in the starting material.
For carrying out the reduction, the starting material can be present in aqueous solution or suspension and the reducing agent added thereto in solid form or dissolved in water. It is preferred to work in a two-phase mixture by adding thereto a polar organic solvent which, at most, is only partly miscible with water, especially butan-2-ol.
The reaction is preferably carried out at a temperature of 40 to 60xc2x0 C. and especially of 50 to 55xc2x0 C. and at a pH of 7 to 9. The reduction is preferably carried out several times and especially 2 to 10 times.
The 9-anthrone-8-glucosides formed are precipitated out by the addition of an acid, for example of sulphuric acid, to a pH value of 4 to 4.5. The temperature should thereby preferably be not more than 40xc2x0 C. In the case of the precipitating out of the anthrone glucosides and in the case of the isolation thereof, for example by filtration, it is preferable to work under an atmosphere of nitrogen in order to avoid an uncontrolled oxidation of these compounds.
The anthrone compounds obtained are now oxidised to the corresponding anthraquinone compounds of the general formula: 
wherein R is COOH or CH2OH. Oxidation agents appropriate for this purpose include, for example, oxygen, peroxide compounds, such as hydrogen peroxide, and manganese, chromium and iron compounds in high oxidation states. It is preferred to use a ferric salt and especially ferric sulphate. It is preferable to work at an elevated temperature but at one below 60xc2x0 C. The formation of undesired and undefinable oxidation products is thereby avoided. After completion of the oxidation, the anthraquinone-8-glucosides are isolated in the usual manner.
The glucose residue in the 8-position of the anthraquinone compounds is split off in acidic solution. It is preferred to work at a temperature of about 85 to 95xc2x0 C. The product obtained is isolated in the usual manner.
It is known to convert sennosides, after acidic hydrolysis, by reaction with ferric chloride directly into rhein (see for example DE-A-27 11 493). However, the yield is thereby only about 10% and, in addition, the rhein formed is difficult to separate.
In the case of the process according to the present invention, the reductive cleavage of the sennosides, the oxidation of the anthrone compounds formed to the corresponding anthraquinone compounds and the splitting off of the glucose residue in the 8-position of the anthraquinone compounds are, in each case, carried out in separate steps. Surprisingly, in this way, rhein is obtained in a yield of 89%. Furthermore, it is possible to carry out the oxidation at modest temperatures so that the formation of undesired and undefinable oxidation products is avoided. Furthermore, when carrying out the reaction, the iron salt used can be recovered almost quantitatively and, after reoxidising, can be used again. The separation of oxidation step and hydrolysis step permits, on the basis of the greater water solubility of the anthrone glucosides in comparison with the aglycones in question, the gently carrying out of the oxidation at ambient temperature or at a temperature below 60xc2x0 C., the otherwise unavoidable formation of undefined by-products thereby being avoided.
The acetylation of the 1,8-dihydroxyanthraquinone compounds obtained takes place in the usual manner. For example, acetylation can be carried out with acetic anhydride in the presence of sodium acetate in the manner described in Arch. Pharm., 241, 607/1903. However, the acetylation can also take place by means of other methods known to the expert, for example by reaction with acetyl chloride or the like.
A liquidxe2x80x94liquid partitioning of the product obtained is carried out in a polar organic solvent which, at most, is only partly miscible with water and an aqueous phase of pH 6.5 to 7.5. Appropriate polar organic solvents include C4-C5-alkanols and C1-C3-dialkyl ketones, for example butan-1-ol, butan-2-ol, isobutanol and butan-2-one, the latter being preferred.
The volume ratio of heavier to lighter phase is, in general, in the range of from 1:2 to 2:1. The lighter phase is a solution of the diacetylanthraquinone compounds in the polar organic solvent. As heavier phase, there is used an aqueous phase of pH 6.5 to 7.5 which is preferably adjusted with a buffer and especially with an acetate buffer.
The liquidxe2x80x94liquid extraction is preferably carried out in countercurrent, the diacetylrhein thereby being introduced into the organic phase in a concentration of about 0.01 M.
After the partitioning, the desired diacetylrhein is present in the heavier phase. It is precipitated out by acidification to a pH value of about 5.2 and then recovered in the usual manner and the diacetylrhein is recrystallised as an alkali metal salt and preferably as potassium salt, the salt then being converted into the insoluble free acid. Alternatively, there can be used a direct recrystallisation from ethyl lactate.
The diacetylrhein obtained in this manner is substantially free from aloe-emodin and derivatives thereof. The content of these impurities thereby still amounts to about 50 ppm (determined by the analysis process described in the following Examples). The content of these impurities can be further reduced when the diacetylrhein obtained is recrystallised in the following manner. The diacetylrhein is converted into an alkali metal salt by treatment with an appropriate base, an appropriate base being, for example, an alkali metal acetate and preferably potassium acetate. It is preferable to use equimolar amounts of base and an aqueous C1-C3-alcohol, for example 80 to 90% ethanol, as reaction medium. The alkali metal salt of diacetylrhein is allowed to crystallise out in the cold, then taken up in an aqueous C1-C3-alcohol and precipitated out by the addition of an acid to a pH value of about 3. The diacetylrhein precipitated out is then isolated in the usual manner and worked up. As a variant a direct recrystallisation can be carried out from ethyl lactate.
The product thus obtained contains less than 20 ppm of the above-mentioned impurities. Furthermore, the product is present in the form of needle-shaped crystals which are especially appropriate for galenical formulation.
The product can be dried in the usual manner. It is preferable first to carry out the drying in a vacuum at a relatively low temperature, for example of not more than 40xc2x0 C., until the water content of the product has decreased to about 3% or less. Subsequently, the temperature can be increased to 70 to 110xc2x0 C.
The present invention is also concerned with the substantially pure diacetylrhein obtainable according to the present invention, as well as with pharmaceutical compositions which contain this compound. The fields of use, the dosage to be administered and appropriate forms of dosaging are known from and described, for example, in U.S. Pat. Nos. 4,244,968, 4,346,103, 4,950,687 and DE-A-27 11 493, as well as in Drugs Exptl. Clin. Res., 6 (1), 53-64/1980.
The following Examples are given for the purpose of illustrating the present invention.